Multiple roles of the nuclear receptors for oxysterols liver X receptor to maintain male fertility

Oxysterol nuclear receptors liver X receptor (LXR)alpha and LXR beta are known to regulate lipid homeostasis in cells exposed to high amounts of cholesterol and/or fatty acids. In order to elucidate the specific and redundant roles of the LXRs in the testis, we explored the reproductive phenotypes of mice deficient of LXR alpha, LXR beta, and both, of which only the lxr alpha;beta(-/-) mice are infertile by 5 months of age. We demonstrate that LXR alpha-deficient mice had lower levels of testicular testosterone that correlated with a higher apoptotic rate of the germ cells. LXR beta-deficient mice showed increased lipid accumulation in the Sertoli cells and a lower proliferation rate of the germ cells. In lxr alpha;beta(-/-) mice, fatty acid metabolism was affected through a decrease of srebp1c and increase in scd1 mRNA expression. The retinoid acid signaling pathway was also altered in lxr alpha;beta(-/-) mice, with a higher accumulation of all-trans retinoid receptor alpha, all-trans retinoid receptor beta, and retinoic aldehyde dehydrogenase-2 mRNA. Combination of these alterations might explain the deleterious phenotype of infertility observed only in lxr alpha;beta(-/-) mice, even though lipid homeostasis seemed to be first altered. Wildtype mice treated with a specific LXR agonist showed an increase of testosterone production involving both LXR isoforms. Altogether, these data identify new roles of each LXR, collaborating to maintain both integrity and functions of the testis.